Set in San Francisco, California, in the early years of the twentieth century, McTeague is the story of a young dentist named McTeague and of his emotional decline. McTeague is introduced to a beautiful, innocent young woman named Trina. Immediately, something is stirred within him, something he has never felt before. McTeague is instantly taken by Trina's beauty and perhaps more so by her innocence. It is a sexual awakening for him. When a dental procedure he is performing on Trina begins to hurt, he cannot bear the thought of causing her pain and agrees to administer an anaesthetic. Once Trina is unconscious, a different side of McTeague wells up. Seeing her helpless, defenceless and so desirable causes McTeague to lose control and to give in to his passions. He kisses her. The kiss serves not to quench his desires but rather to amplify it. When the effects of the anaesthetic wear off and Trina awakens, McTeague offers her a hasty proposal of marriage. Trina is appalled, refuses the proposition and leaves. This is the beginning of a tumultuous relationship that will last for the duration of their lives.

Trina's reaction does not sway McTeague away from his affections for her. One day, McTeague decides to confess his feelings for Trina to Marcus, her cousin. Marcus insists they call on Trina together, and the relationship between McTeague and Trina takes a turn. They begin courting and are eventually married. On the night they announce their engagement, the couple learns that a lottery ticket Trina purchased on the day she met McTeague has won the grand prize of fifteen thousand dollars, an event that will prove to be more disastrous than fortuitous.

Immediately following the McTeague wedding, Trina's parents leave the San Francisco area to follow a job opportunity in the southern part of the state. Trina is essentially left alone with her husband, her lottery winnings and her new life. As time passes, the newlyweds turn into a more settled-in married couple. The transformation doesn't stop there, however. Each falls into an ever-darkening spiral toward the ugly side of humanity, revealing a second self that is completely set apart from the person we meet at the beginning of the novel.

The novel is, as a whole, a depiction of the savage side of humanity, of the things that turn men into beasts: greed, despair, jealousy, rage and loneliness. The novel examines the idea that our actions and traits are not entirely determined by our conscious decisions. We are influenced by our actions and by a power that is larger than our existence.